Intrinsic to the hypothalamic-pituitary-thyroid axis (HPTA) and the leptin-melanocortin system (LMS) are homeostatic and feedback mechanisms that maintain circulating and tissue levels of thyroxine (T4), 3,3',5- triiodothyronine (T3) and Leptin (LEP) within strict limits. These endocrine systems in turn influence a host of physiological processes critical to the metabolic health and adaptability of the organism. The type 3 deiodinase (DIO3) functions to inactivate T4 and T3 in tissues and is coded by a gene that is imprinted in mice and humans. DIO3 is highly expressed in the maternal-fetal unit and in the neonate, where it plays a critical role in ensuring that concentrations of TH are optimal for development and for the programming of the HPTA and the LMS. Thus, mice deficient in DIO3 have altered serum TH levels, marked dysfunction of the hypothalamus, pituitary and thyroid glands and adipose tissue. Our preliminary data suggest that a developmental excess of T3 modifies the epigenetic information of the germ line, including the Dio3 locus and that of other developmental genes. This leads in subsequent generations to alterations in the ontogeny and set points of the HPTA and the LMS, with consequences for the susceptibility to metabolic disease. Thus, this proposal seeks to investigate the hypothesis that developmental overexposure to T3 elicits changes in the transgenerational epigenetic inheritance at the Dio3 locus and at other relevant loci and influences in descendants the programming of the HPTA and LMS and the regulation of TH action and energy balance throughout life. Specifically, and based on our data concerning the alterations in the epigenetic information of germ line caused by a developmental excess of T3, we propose herein experiments to: (1) Define the patterns of inheritance of altered epigenetic marks at the Dio3 locus and at other gene loci of relevance to the development of the HPTA and the LMS that are caused by an ancestral developmental overexposure to T3; (2) Delineate the phenotypic consequences of such altered epigenetic inheritance for the ontogeny, function and physiological adaptability of the HPTA and the LMS. Notably, this heritable process may represent a novel transgenerational mechanism that impacts the degree of plasticity by which the HPTA and the LMS adapt to homeostatic challenges, reducing or exacerbating the propensity to develop obesity. In addition, given the importance of the DIO3 in modulating the intracellular levels of TH and the breadth of epigenetic alterations caused by an excess of T3, this new paradigm implies an additional, heritable component that may be of significance to other disease states affecting mental health or reproductive function.